The MAD1 1673 G→A polymorphism alters the function of the mitotic spindle assembly checkpoint and is associated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian cancer
BACKGROUNDMitotic arrest deficient 1 (MAD1), a protein of the mitotic spindle assembly checkpoint (SAC), recognizes MAD2 through two leucine zippers, transporting and activating MAD2, which promotes a metaphase arrest signal. A single nucleotide polymorphism of MAD1 was found to affect the SAC funct...
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| Veröffentlicht in: | Pharmacogenetics and genomics 2013-04, Vol.23 (4), p.190-199 |
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| creator | Santibáñez, Miguel Gallardo, Dolores Morales, Flavia López, Alejandro Prada, Diddier Mendoza, Julia Castro, Clementina de León, David Cantú Oñate, Luis F Perez, Delia Mohar, Alejandro Herrera, Luis A |
| description | BACKGROUNDMitotic arrest deficient 1 (MAD1), a protein of the mitotic spindle assembly checkpoint (SAC), recognizes MAD2 through two leucine zippers, transporting and activating MAD2, which promotes a metaphase arrest signal. A single nucleotide polymorphism of MAD1 was found to affect the SAC function that could be involved in a poor response to therapeutic agents that alter the dynamics of microtubules.
OBJECTIVEThe aim of this study was to examine the relationship of the polymorphism MAD1 1673 G→A (rs1801368) with the efficiency of the SAC and the generation of aneuploidies and with the therapeutic response of patients with ovarian cancer.
METHODSThe polymorphism was evaluated in 144 healthy individuals and 91 patients. Mitotic arrest and the presence of errors in segregation were analyzed in cultured human lymphocytes treated with nocodazole and paclitaxel. Errors in segregation were also evaluated in 27 biopsies of patients.
RESULTSAllele frequencies in healthy individuals were G50%, A50%, whereas in the patients they were G38%, A62% (P |
| doi_str_mv | 10.1097/FPC.0b013e32835ea08a |
| format | Article |
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OBJECTIVEThe aim of this study was to examine the relationship of the polymorphism MAD1 1673 G→A (rs1801368) with the efficiency of the SAC and the generation of aneuploidies and with the therapeutic response of patients with ovarian cancer.
METHODSThe polymorphism was evaluated in 144 healthy individuals and 91 patients. Mitotic arrest and the presence of errors in segregation were analyzed in cultured human lymphocytes treated with nocodazole and paclitaxel. Errors in segregation were also evaluated in 27 biopsies of patients.
RESULTSAllele frequencies in healthy individuals were G50%, A50%, whereas in the patients they were G38%, A62% (P<0.05). The percentage of cells with mitotic arrest was higher among GG cells (P<0.05). The frequency of micronuclei and nondisjunction events increased in AA cells (P<0.05). Tumors from polymorphic patients had a higher percentage of aneuploid cells (P<0.05). The GG patients showed a higher biochemical response, optimal cytoreduction, and sensitivity to the treatment. There were no differences in progression-free or overall survival between both groups.
CONCLUSIONThe polymorphism MAD1 1673 G→A affects SAC functionality, increasing the frequency of aneuploid cells. This polymorphism modifies the response to agents that alter the dynamics of microtubules in patients with ovarian cancer.</description><identifier>ISSN: 1744-6872</identifier><identifier>EISSN: 1744-6880</identifier><identifier>DOI: 10.1097/FPC.0b013e32835ea08a</identifier><identifier>PMID: 23407047</identifier><language>eng</language><publisher>United States: Lippincott Williams & Wilkins, Inc</publisher><subject>Biomarkers, Pharmacological ; Calcium-Binding Proteins - genetics ; Carcinoma, Ovarian Epithelial ; Cell Cycle Proteins - genetics ; Chromosomal Instability - drug effects ; Chromosomal Instability - genetics ; Female ; Genetic Association Studies ; Humans ; M Phase Cell Cycle Checkpoints - drug effects ; M Phase Cell Cycle Checkpoints - genetics ; Mad2 Proteins ; Microtubules - pathology ; Neoplasm Staging ; Neoplasms, Glandular and Epithelial - drug therapy ; Neoplasms, Glandular and Epithelial - genetics ; Neoplasms, Glandular and Epithelial - pathology ; Nocodazole - pharmacology ; Nuclear Proteins - genetics ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - pathology ; Paclitaxel - pharmacology ; Polymorphism, Single Nucleotide ; Repressor Proteins - genetics</subject><ispartof>Pharmacogenetics and genomics, 2013-04, Vol.23 (4), p.190-199</ispartof><rights>2013 Lippincott Williams & Wilkins, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356a-ec205c382ebbe0098faf170c6ee93bfd5d89b85f618d3541f92d693cb8d75d093</citedby><cites>FETCH-LOGICAL-c356a-ec205c382ebbe0098faf170c6ee93bfd5d89b85f618d3541f92d693cb8d75d093</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23407047$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Santibáñez, Miguel</creatorcontrib><creatorcontrib>Gallardo, Dolores</creatorcontrib><creatorcontrib>Morales, Flavia</creatorcontrib><creatorcontrib>López, Alejandro</creatorcontrib><creatorcontrib>Prada, Diddier</creatorcontrib><creatorcontrib>Mendoza, Julia</creatorcontrib><creatorcontrib>Castro, Clementina</creatorcontrib><creatorcontrib>de León, David Cantú</creatorcontrib><creatorcontrib>Oñate, Luis F</creatorcontrib><creatorcontrib>Perez, Delia</creatorcontrib><creatorcontrib>Mohar, Alejandro</creatorcontrib><creatorcontrib>Herrera, Luis A</creatorcontrib><title>The MAD1 1673 G→A polymorphism alters the function of the mitotic spindle assembly checkpoint and is associated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian cancer</title><title>Pharmacogenetics and genomics</title><addtitle>Pharmacogenet Genomics</addtitle><description>BACKGROUNDMitotic arrest deficient 1 (MAD1), a protein of the mitotic spindle assembly checkpoint (SAC), recognizes MAD2 through two leucine zippers, transporting and activating MAD2, which promotes a metaphase arrest signal. A single nucleotide polymorphism of MAD1 was found to affect the SAC function that could be involved in a poor response to therapeutic agents that alter the dynamics of microtubules.
OBJECTIVEThe aim of this study was to examine the relationship of the polymorphism MAD1 1673 G→A (rs1801368) with the efficiency of the SAC and the generation of aneuploidies and with the therapeutic response of patients with ovarian cancer.
METHODSThe polymorphism was evaluated in 144 healthy individuals and 91 patients. Mitotic arrest and the presence of errors in segregation were analyzed in cultured human lymphocytes treated with nocodazole and paclitaxel. Errors in segregation were also evaluated in 27 biopsies of patients.
RESULTSAllele frequencies in healthy individuals were G50%, A50%, whereas in the patients they were G38%, A62% (P<0.05). The percentage of cells with mitotic arrest was higher among GG cells (P<0.05). The frequency of micronuclei and nondisjunction events increased in AA cells (P<0.05). Tumors from polymorphic patients had a higher percentage of aneuploid cells (P<0.05). The GG patients showed a higher biochemical response, optimal cytoreduction, and sensitivity to the treatment. There were no differences in progression-free or overall survival between both groups.
CONCLUSIONThe polymorphism MAD1 1673 G→A affects SAC functionality, increasing the frequency of aneuploid cells. This polymorphism modifies the response to agents that alter the dynamics of microtubules in patients with ovarian cancer.</description><subject>Biomarkers, Pharmacological</subject><subject>Calcium-Binding Proteins - genetics</subject><subject>Carcinoma, Ovarian Epithelial</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Chromosomal Instability - drug effects</subject><subject>Chromosomal Instability - genetics</subject><subject>Female</subject><subject>Genetic Association Studies</subject><subject>Humans</subject><subject>M Phase Cell Cycle Checkpoints - drug effects</subject><subject>M Phase Cell Cycle Checkpoints - genetics</subject><subject>Mad2 Proteins</subject><subject>Microtubules - pathology</subject><subject>Neoplasm Staging</subject><subject>Neoplasms, Glandular and Epithelial - drug therapy</subject><subject>Neoplasms, Glandular and Epithelial - genetics</subject><subject>Neoplasms, Glandular and Epithelial - pathology</subject><subject>Nocodazole - pharmacology</subject><subject>Nuclear Proteins - genetics</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Paclitaxel - pharmacology</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Repressor Proteins - genetics</subject><issn>1744-6872</issn><issn>1744-6880</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU2O1DAQhSMEYoaBGyDkJZse7DiJnWWrmR-kQbAY1pFjVxQzjm1sp1u5AAfgiByBE4z7h1mwYFWvVK--t3hF8ZbgS4Jb9uH66-YS95hQoCWnNQjMxbPinLCqWjWc4-dPmpVnxasYv2NMm7YqXxZnJa0wwxU7L_7cj4A-rz8SRBpG0c3vn7_WyDuzTC74UccJCZMgRJSyb5itTNpZ5IbDPunkkpYoem2VASRihKk3C5IjyAfvtE1IWIV03J-c1CKBQjudRiTQzoUIKED0zmaRHMqQ-cjP_5PLCUH45UCIYKNOeqvTsnemACJNkPHaIi-SzjKewGorrMwx4PMKRguD3FYELTJ2fwmvixeDMBHenOZF8e366n5zu7r7cvNps75bSVo3YgWyxLWkvIS-B4xbPoiBMCwbgJb2g6oVb3teDw3hitYVGdpSNS2VPVesVrilF8X7I9cH92OGmLpJRwnGCAtujh2hpCa0ZqzJ1upolcHFGGDofNCTCEtHcLdvu8ttd_-2nd_enRLmfgL19PS33mzgR8POHVp8MPMOQjdCLnX8P_sRDPvA8g</recordid><startdate>201304</startdate><enddate>201304</enddate><creator>Santibáñez, Miguel</creator><creator>Gallardo, Dolores</creator><creator>Morales, Flavia</creator><creator>López, Alejandro</creator><creator>Prada, Diddier</creator><creator>Mendoza, Julia</creator><creator>Castro, Clementina</creator><creator>de León, David Cantú</creator><creator>Oñate, Luis F</creator><creator>Perez, Delia</creator><creator>Mohar, Alejandro</creator><creator>Herrera, Luis A</creator><general>Lippincott Williams & Wilkins, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201304</creationdate><title>The MAD1 1673 G→A polymorphism alters the function of the mitotic spindle assembly checkpoint and is associated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian cancer</title><author>Santibáñez, Miguel ; Gallardo, Dolores ; Morales, Flavia ; López, Alejandro ; Prada, Diddier ; Mendoza, Julia ; Castro, Clementina ; de León, David Cantú ; Oñate, Luis F ; Perez, Delia ; Mohar, Alejandro ; Herrera, Luis A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356a-ec205c382ebbe0098faf170c6ee93bfd5d89b85f618d3541f92d693cb8d75d093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Biomarkers, Pharmacological</topic><topic>Calcium-Binding Proteins - genetics</topic><topic>Carcinoma, Ovarian Epithelial</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Chromosomal Instability - drug effects</topic><topic>Chromosomal Instability - genetics</topic><topic>Female</topic><topic>Genetic Association Studies</topic><topic>Humans</topic><topic>M Phase Cell Cycle Checkpoints - drug effects</topic><topic>M Phase Cell Cycle Checkpoints - genetics</topic><topic>Mad2 Proteins</topic><topic>Microtubules - pathology</topic><topic>Neoplasm Staging</topic><topic>Neoplasms, Glandular and Epithelial - drug therapy</topic><topic>Neoplasms, Glandular and Epithelial - genetics</topic><topic>Neoplasms, Glandular and Epithelial - pathology</topic><topic>Nocodazole - pharmacology</topic><topic>Nuclear Proteins - genetics</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Paclitaxel - pharmacology</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Repressor Proteins - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Santibáñez, Miguel</creatorcontrib><creatorcontrib>Gallardo, Dolores</creatorcontrib><creatorcontrib>Morales, Flavia</creatorcontrib><creatorcontrib>López, Alejandro</creatorcontrib><creatorcontrib>Prada, Diddier</creatorcontrib><creatorcontrib>Mendoza, Julia</creatorcontrib><creatorcontrib>Castro, Clementina</creatorcontrib><creatorcontrib>de León, David Cantú</creatorcontrib><creatorcontrib>Oñate, Luis F</creatorcontrib><creatorcontrib>Perez, Delia</creatorcontrib><creatorcontrib>Mohar, Alejandro</creatorcontrib><creatorcontrib>Herrera, Luis A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Pharmacogenetics and genomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Santibáñez, Miguel</au><au>Gallardo, Dolores</au><au>Morales, Flavia</au><au>López, Alejandro</au><au>Prada, Diddier</au><au>Mendoza, Julia</au><au>Castro, Clementina</au><au>de León, David Cantú</au><au>Oñate, Luis F</au><au>Perez, Delia</au><au>Mohar, Alejandro</au><au>Herrera, Luis A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The MAD1 1673 G→A polymorphism alters the function of the mitotic spindle assembly checkpoint and is associated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian cancer</atitle><jtitle>Pharmacogenetics and genomics</jtitle><addtitle>Pharmacogenet Genomics</addtitle><date>2013-04</date><risdate>2013</risdate><volume>23</volume><issue>4</issue><spage>190</spage><epage>199</epage><pages>190-199</pages><issn>1744-6872</issn><eissn>1744-6880</eissn><abstract>BACKGROUNDMitotic arrest deficient 1 (MAD1), a protein of the mitotic spindle assembly checkpoint (SAC), recognizes MAD2 through two leucine zippers, transporting and activating MAD2, which promotes a metaphase arrest signal. A single nucleotide polymorphism of MAD1 was found to affect the SAC function that could be involved in a poor response to therapeutic agents that alter the dynamics of microtubules.
OBJECTIVEThe aim of this study was to examine the relationship of the polymorphism MAD1 1673 G→A (rs1801368) with the efficiency of the SAC and the generation of aneuploidies and with the therapeutic response of patients with ovarian cancer.
METHODSThe polymorphism was evaluated in 144 healthy individuals and 91 patients. Mitotic arrest and the presence of errors in segregation were analyzed in cultured human lymphocytes treated with nocodazole and paclitaxel. Errors in segregation were also evaluated in 27 biopsies of patients.
RESULTSAllele frequencies in healthy individuals were G50%, A50%, whereas in the patients they were G38%, A62% (P<0.05). The percentage of cells with mitotic arrest was higher among GG cells (P<0.05). The frequency of micronuclei and nondisjunction events increased in AA cells (P<0.05). Tumors from polymorphic patients had a higher percentage of aneuploid cells (P<0.05). The GG patients showed a higher biochemical response, optimal cytoreduction, and sensitivity to the treatment. There were no differences in progression-free or overall survival between both groups.
CONCLUSIONThe polymorphism MAD1 1673 G→A affects SAC functionality, increasing the frequency of aneuploid cells. This polymorphism modifies the response to agents that alter the dynamics of microtubules in patients with ovarian cancer.</abstract><cop>United States</cop><pub>Lippincott Williams & Wilkins, Inc</pub><pmid>23407047</pmid><doi>10.1097/FPC.0b013e32835ea08a</doi><tpages>10</tpages></addata></record> |
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| ispartof | Pharmacogenetics and genomics, 2013-04, Vol.23 (4), p.190-199 |
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| source | MEDLINE; Journals@Ovid Complete |
| subjects | Biomarkers, Pharmacological Calcium-Binding Proteins - genetics Carcinoma, Ovarian Epithelial Cell Cycle Proteins - genetics Chromosomal Instability - drug effects Chromosomal Instability - genetics Female Genetic Association Studies Humans M Phase Cell Cycle Checkpoints - drug effects M Phase Cell Cycle Checkpoints - genetics Mad2 Proteins Microtubules - pathology Neoplasm Staging Neoplasms, Glandular and Epithelial - drug therapy Neoplasms, Glandular and Epithelial - genetics Neoplasms, Glandular and Epithelial - pathology Nocodazole - pharmacology Nuclear Proteins - genetics Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology Paclitaxel - pharmacology Polymorphism, Single Nucleotide Repressor Proteins - genetics |
| title | The MAD1 1673 G→A polymorphism alters the function of the mitotic spindle assembly checkpoint and is associated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian cancer |
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